Impaired Spermatogenesis, Muscle, and Erythrocyte Function in U12 Intron Splicing-Defective Zrsr1 Mutant Mice

Publication date: 3 April 2018
Source:Cell Reports, Volume 23, Issue 1
Author(s): Keiko Horiuchi, Serafín Perez-Cerezales, Panagiotis Papasaikas, Priscila Ramos-Ibeas, Angela Patricia López-Cardona, Ricardo Laguna-Barraza, Noelia Fonseca Balvís, Eva Pericuesta, Raul Fernández-González, Benjamín Planells, Alberto Viera, Jose Angel Suja, Pablo Juan Ross, Francisco Alén, Laura Orio, Fernando Rodriguez de Fonseca, Belén Pintado, Juan Valcárcel, Alfonso Gutiérrez-Adán
The U2AF35-like ZRSR1 has been implicated in the recognition of 3′ splice site during spliceosome assembly, but ZRSR1 knockout mice do not show abnormal phenotypes. To analyze ZRSR1 function and its precise role in RNA splicing, we generated ZRSR1 mutant mice containing truncating mutations within its RNA-recognition motif. Homozygous mutant mice exhibited severe defects in erythrocytes, muscle stretch, and spermatogenesis, along with germ cell sloughing and apoptosis, ultimately leading to azoospermia and male sterility. Testis RNA sequencing (RNA-seq) analyses revealed increased intron retention of both U2- and U12-type introns, including U12-type intron events in genes with key functions in spermatogenesis and spermatid development. Affected U2 introns were commonly found flanking U12 introns, suggesting functional cross-talk between the two spliceosomes. The splicing and tissue defects observed in mutant mice attributed to ZRSR1 loss of function suggest a physiological role for this factor in U12 intron splicing.

Graphical abstract

Teaser

Horiuchi et al. report that mutations in Zrsr1 cause defects in blood, muscle, and spermatogenesis. The molecular basis for the spermatogenesis defect is the Zrsr1 involvement in processing U12-type introns (minor splicing), causing retention of most of the U12 introns examined.


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